In this R03 application, we propose to complete first of the two phases of our strategy to integrate both biological and computational methods to a coherent and predictive program for the effects of a chemical mixture (methylmercury and PCBs) on central nervous system (CNS) development. Phase 1 (this project) involves: (1) In vitro neuronal cell culture studies on molecular endpoints related to the mechanism(s) of neurodevelopmental changes leading to neurobehavioral deficit (i.e., Specific Aim 1); and (2) Constructing an interactive physiologically-based pharmacokinetic/pharmacodynamic (PBPK/PD) model based on the above in vitro mechanistic studies as well as in vivo pharmacokinetic studies (i.e., Specific Aim 2). Phase 2, which will be the validation neurobehavioral studies, will be the basis of a follow-up R01 grant proposal to complete the development of a predictive approach. Thus, the long-term objective of this proposal is to establish an integrated, predictive approach for the study of mechanisms underlying the interactive effects of chemical mixtures on CNS development. Our hypothesis is that MeHg and PCBs synergistically disrupt spatial learning and memory, in part, by interfering with the glutamate-mediated, calcium-dependent development of hippocampal neuronal networks. The uniqueness of this proposal resides in: (1) mechanistic studies on toxicologic interactions in a chemical mixture; and (2) the integration of the state-of-the-art experimental toxicology with computer modeling. We believe that this project will have a high probability of success because of the expertise assembled: Yang (toxicology of chemical mixtures; PBPK/PD modeling); Ou (molecular neurotoxicology), Andersen (PBPK/PD modeling) and Handa (molecular neurobiology; neurobehavioral studies).